The central theme of this proposal is the total synthesis of Gephyrotoxin 287C, one of many poison dart frog alkaloids with intriguing and specific neuroexcitatory properties. This broad class of natural products is structurally diverse and complex, and many of these alkaloids possess powerful yet highly specific biological activity, the detailed investigation of which has considerable therapeutic implications. However, as they are often isolated from natural sources in meager quantities, a laboratory synthesis proves desirable and provides many additional benefits, such as confirmation of structure and elucidation of biosynthetic/metabolic pathways. More importantly, it can supply sufficient material for biological testing, and allows aces to structural analogs that may in turn reveal the key pharmacophore. Therefore, continued development of new and varied methodology to aid in the total synthesis of alkaloid natural products remains of the utmost importance. The specific approach proposed herein involves one such nascent methodology - the utilization of N-substituted oxazolones as the dienophilic component in a novel intramolecular Diels-Alder cycloaddition. As this is a reaction originally developed in the P.I.'s laboratories, the proposed studies have ample precedent and preliminary results are supportive. The planned route hinges upon rapid construction of a densely functionalized cis-fused decahydroquinoline core containing 3 of the 5 required stereocenters of gephyrotoxin. Once in hand, this framework will serve as the key heterocyclic scaffold for all further elaboration to the final target itself. A number of innovative strategies will be employed to achieve this, including a 2-step cyclopropanation-ring scission approach to regio- and stereoselective installation of a required C6 substituent, and the tandem closure of a pyrrolidine ring by E2 excision of an oxazolidinone moiety followed by Michael cyclization. These studies, to be investigated in parallel, will employ a combination of new methodology and established precedent. Once the specific nature of these reaction paths is established, a direct route to the target will be finalized. Although early model studies will be pursued in racemic fashion, an enantioselective synthesis using an asymmetric induction technique is also presented. Finally, extrapolation to further 2- epi-cis-fused decahydroquinoline targets is subsequently planned. These efforts toward gephyrotoxin will therefore aid in the continued development of novel synthetic methodology for the total synthesis of bioactive alkaloids, and in doing so will provide numerous structurally related analogs for biological evaluation. PUBLIC HEALTH RELEVANCE: This proposal addresses the total synthesis of the alkaloid Gephrotoxin 287C, a poison dart frog toxin with intriguing neurological activity and thus therapeutic potential. The described route is based on novel synthetic methodology that is both versatile and will result in the provision of numerous structural analogs. This in turn will enable a detailed comparison with the natural product, particularly in terms of structure and the specific bioactivity associated with several neurological disease states.